Vascular oxidant stress is a common feature of multiple cardiovascular diseases, but therapeutic approaches based on administration of antioxidants have been surprisingly disappointing. As a result, there is growing interest in direct upregulation of endogenous antioxidant defenses as a potential therapeutic strategy in pathological conditions associated with oxidant stress. One attractive target for these strategies is the master antioxidant and cell protective transcription factor nuclear factor (erythroid- derivd 2)-like-2 (NRF2), which regulates the expression of multiple antioxidant and cell protective genes that are potentially involved in over 200 different human diseases. This project will use a new and powerful experimental model (the Nrf2(-/-) knockout rat) to test the overall hypothesis that down-regulation of NRF2-regulated enzymes plays a major role in vascular oxidant stress occurring with high salt (HS) diet; and that prevention of salt-induced ANG II suppression or administration of compounds known to upregulate the NRF2 system will ameliorate the endothelial dysfunction and impaired angiogenesis associated with elevated dietary salt intake. Specific Aim #1 is to test the hypothesis that restoring normal plasma ANG II levels and administration of mas receptor agonists ameliorate vascular oxidant stress and endothelial dysfunction in HS-fed animals via a common pathway (ERK 1/2 activation), leading to activation of the NRF2 antioxidant defense system. Specific Aim #2 is to test the hypothesis that restoration of normal plasma ANG II levels and administration of mas receptor agonists prevent salt-induced microvascular rarefaction via a common pathway (ERK 1/2 activation), leading to upregulation of NRF2-mediated antioxidant defense mechanisms; and that direct upregulation of the NRF2 system will improve angiogenic responses in the presence of salt-induced ANG II suppression. We have expanded the study to include male and female rats in light of the importance of understanding sex-related differences in cardiovascular disease and the relative scarcity of information regarding NRF2 antioxidant defenses in females. Because of the pervasive importance of NRF2 in regulating antioxidant defenses, these studies will provide valuable insight into the mechanisms of salt-induced oxidant stress and vascular dysfunction; and could lead to the development of effective therapeutic approaches to cardiovascular diseases based on direct upregulation of NRF2-regulated antioxidant defense mechanisms.